Abstract 2498: Differential rapamycin sensitivity distinguishes two distinct populations of tumor cells in murine glioma

Abstract

Abstract Solid tumors are complex ecosystems, composed of a heterogeneous ensemble of cells that comprise the tumor mass (neoplastic compartment) and the surrounding stroma (non-neoplastic compartment). Currently, research efforts are aimed at defining the individual contributions of each cell type to tumor development and maintenance. Previous studies using a genetically-engineered mouse model of Neurofibromatosis type 1 (NF1)-associated optic glioma have underscored the critical role of one stromal cell type (microglia) in the growth of these tumors. In the current study, we analyze neoplastic cell heterogeneity and demonstrate that two distinct proliferating populations of neoplastic cells exist in the tumor. These distinct cell types, neuroglial progenitors and differentiated astrocytes, are distinguished by their sensitivity to rapamycin. The molecular basis for this differential sensitivity to rapamycin reflects dramatic differences in mammalian target of rapamycin (mTOR) complex protein expression and basal mTOR activation. We leverage this cell type-specific sensitivity to target neuroglial progenitor cells in the tumor and inhibit optic glioma formation in vivo. Collectively, these findings emphasize the importance of cellular diversity in glioma formation and growth, and highlight the importance of developing novel treatment strategies that co-target multiple cell populations for maximal therapeutic benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2498. doi:1538-7445.AM2012-2498